Distinguishing Encephaloclastic Lesions Resulting From Primary or Secondary Pyruvate Dehydrogenase Deficiency From Other Neonatal or Infantile Cavitary Brain Lesions.

The central nervous system (CNS) is a highly complex and energy-dependent organ that is subject to a wide variety of metabolic, hypoxic-ischemic, and infectious insults that result in cystic changes. Diagnosis of metabolic defects causing extensive cystic changes is particularly challenging for the pediatric pathologist, due to the rarity of these conditions. Pyruvate dehydrogenase (PDH) deficiency is one of the most common etiologies of congenital lactic acidosis, caused by mutations in subunits of the large mitochondrial matrix complex, and characterized by periventricular cysts, although few detailed reports focusing on neuropathologic findings exist. In addition, rare defects in other mitochondrial enzymes such as short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1 gene) can cause secondary PDH deficiency and present with neonatal lactic acidosis, but neuropathological findings have never been reported. Nonmetabolic conditions can also produce CNS cystic lesions, primarily in newborns. The pathologist must therefore distinguish between these etiologically disparate conditions which can produce CNS cavitary lesions. Here, we compare and contrast the gross and microscopic findings of cysts associated with cases of PDH and SCEH deficiencies with other neonatal cystic brain diseases including periventricular leukomalacia, neonatal Alexander disease, Canavan disease, and a case of cysts associated with a vascular abnormality. Our studies show that PDH and SCEH deficiencies are not grossly or histologically distinguishable from each other and both are associated with smooth-walled cysts largely limited to the telencephalic germinal matrix. Both show an absence of prominent hemosiderin deposits, Rosenthal fibers, vacuolization of the white matter, and gliosis or axonal damage in the surrounding parenchyma. These features can help distinguish PDH/SCEH deficiency from other pediatric/neonatal cystic CNS disorders, especially those produced by hypoxic ischemic conditions. Cysts, usually bilateral, confined to the telencephalic germinal matrix should elicit metabolic and genetic testing to appropriately diagnose PDH and SCEH and distinguish them from each other.

Pyruvate dehydrogenase deficiency. / Pyruvatdehydrogenase-mangel.

Pyruvate dehydrogenase deficiency is a rare mitochondrial disease leading to energy deficiency in the cells. This particularly affects the central nervous system, resulting in a broad range of neurological symptoms.

Pyruvate dehydrogenase deficiency caused by a new mutation of PDHX gene in two Moroccan patients.

Pyruvate dehydrogenase deficiency is one of the genetic defects of mitochondrial energy metabolism. Clinical features are heterogeneous, ranging from fatal lactic acidosis in the newborn period to chronic neurodegenerative abnormalities. Most cases have mutations in the gene for the E1alpha subunit of the pyruvate dehydrogenase complex. Primary defects of the E3 binding protein component of the pyruvate dehydrogenase complex are rarier. We describe two unrelated Moroccan patients with the same new mutation c.1182 + 2T > C in the E3 binding protein gene PDHX and different clinical forms.

Pyruvate dehydrogenase deficiency and epilepsy.

The pyruvate dehydrogenase complex (PDHc) is a mitochondrial matrix multienzyme complex that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the conversion of pyruvate into acetyl-CoA. PDHc deficiency is one of the commoner metabolic disorders of lactic acidosis presenting with neurological phenotypes that vary with age and gender. In this mini-review, we postulate mechanisms of epilepsy in the setting of PDHc deficiency using two illustrative cases (one with pyruvate dehydrogenase complex E1-alpha polypeptide (PDHA1) deficiency and the second one with pyruvate dehydrogenase complex E1-beta subunit (PDHB) deficiency (a rare subtype of PDHc deficiency)) and a selected review of published case series. PDHc plays a critical role in the pathway of carbohydrate metabolism and energy production. In severe deficiency states the resulting energy deficit impacts on brain development in utero resulting in structural brain anomalies and epilepsy. Milder deficiency states present with variable manifestations that include cognitive delay, ataxia, and seizures. Epileptogenesis in PDHc deficiency is linked to energy failure, development of structural brain anomalies and abnormal neurotransmitter metabolism. The use of the ketogenic diet bypasses the metabolic block, by providing a direct source of acetyl-CoA, leading to amelioration of some symptoms. Genetic counseling is essential as PDHA1 deficiency (commonest defect) is X-linked although females can be affected due to unfavorable lyonization, while PDHB and PDH phosphatase (PDP) deficiencies (much rarer defects) are of autosomal recessive inheritance. Research is in progress for looking into animal models to better understand pathogenesis and management of this challenging disorder.

A technical surgery for refractory gastroparesis in a patient with a mitochondrial disorder.

Gastroparesis is a symptomatic chronic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. Gastroparesis has been associated with various diseases and may occur as part of a mitochondrial disorder. In a patient with pyruvate dehydrogenase complex deficiency, which is associated with abnormal mitochondrial metabolism, intragastric liquids were retained massively and gastroparesis was diagnosed by demonstrating delayed gastric emptying. For an atonic stomach with impaired fundic distention, partial gastric plication, modified stomach-partitioning gastrojejunostomy using the stapled gastrectomy with Braun's anastomosis, antireflux gastroplasty with stapled wedge, and re-gastrostomy were performed. After operation, intragastric liquids were reduced remarkably and delayed gastric emptying was improved. She was doing well and discharged uneventfully. Our technical surgery reported improvement in delayed gastric emptying and we confirm the benefits of this operation.

Multiple presentation of mitochondrial disorders.

The aim of this study was to assess the heterogeneous clinical presentations of children with mitochondrial disorders evaluated at a metabolic neurogenetic clinic. The charts of 36 children with highly suspected mitochondrial disorders were reviewed. Thirty one children were diagnosed as having a mitochondrial disorder, based on a suggestive clinical presentation and at least one of the accepted laboratory criteria; however, in five children with no laboratory criteria the diagnosis remained probable. All of the patients had nervous system involvement. Twenty seven patients also had dysfunction of other systems: sensory organs in 15 patients, cardiovascular system in five, gastrointestinal system in 20, urinary system in four, haematopoietic system in four, and endocrine system in nine. The clinical presentation was compatible with an established syndrome in only 15 children. Severe lactic acidosis or ragged red muscle fibres were encountered in very few patients. These results suggest that mitochondrial disorders should be evaluated in children presenting with a complex neurological picture or multisystem involvement.

Hypothesis on cellular ATP depletion and adenosine release as causes of heart failure and vasodilatation in cardiovascular beriberi.

Cardiovascular beriberi is a syndrome caused by thiamine deficiency and characterized by systemic vasodilatation, heart failure and lactic acidosis. The occurrence of heart failure and vasodilatation is yet unexplained: neither theoretical nor experimental data are known. In this article, it is suggested that a fall of cellular ATP levels causes heart failure and that the release of adenosine is the cause of vasodilatation.

MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect.

MR studies were correlated with biochemical results in nine children who presented with lactic acidosis and/or abnormal MR findings in the basal ganglia. Neurologic development was delayed in all nine children. Seven of these patients were diagnosed as having subacute necrotizing encephalomyelopathy (SNE, or Leigh syndrome) on the basis of history, clinical findings, and biochemical studies; of the remaining two, one had congenital lactic acidosis and the other had familial bilateral striatal necrosis with no known biochemical correlate. Although the clinical presentation of these patients was similar, we found distinctive MR abnormalities in characteristic locations in the seven patients with SNE, with or without detectable specific mitochondrial enzyme deficiency in cultured skin fibroblast assays. In our case studies of SNE patients with detectable enzyme deficiency states, defects in pyruvate dehydrogenase complex and cytochrome c oxidase have been found. The MR finding of note in SNE is the remarkably symmetrical involvement, most frequently of the putamen. In our study, lesions were also commonly found in the globus pallidus and the caudate nucleus, but never in the absence of putaminal abnormalities. Other areas of involvement included the paraventricular white matter, corpus callosum, substantia nigra, decussation of superior cerebellar peduncles, periaqueductal region, and brainstem. In patients who present with lactic acidosis and whose MR findings show symmetrical abnormalities in the brain, but with sparing of the putamen, the diagnosis of SNE is in doubt.